Western Veterinary Conference 2013 S15B FIXING URINARY INCONTINENCE IN DOGS - WHAT ARE YOUR OPTIONS? Dennis J. Chew, DVM Dipl. ACVIM (Internal Medicine) The Ohio State University Columbus, OH, USA Primary sphincter mechanism incompetence (PSMI) PSMI is the most common cause of urinary incontinence in adult female dogs seen in primary care practice1. Incontinence in spayed female dogs previously was called hormoneresponsive, or estrogen-responsive, incontinence. This occurs an average of 3 years after ovariohysterectomy in approximately 20% of female dogs neutered between their first and second heat cycles; in dogs spayed before their first estrus, the incidence is reported to be 9.7%2. 5.1% of bitches in another report were found to have spay-related urinary incontinence3. No association of increased risk to develop urinary incontinence was shown in a case control study of 202 incontinent female dogs neutered between 3 and 6 months of age4. Female dogs neutered before 3 months of age however were shown to have twice the risk to develop urinary incontinence before 6 years of age compared to neutering when older than 3 months5. The main mechanism for the development of urinary incontinence with PSMI has traditionally been attributed to low urethral closure pressure, though some dogs have a bladder component to this form of urinary incontinence6. Urethral closure pressure is decreased 12 to 18 months following spaying in normal dogs 7-9 and it is speculated that this pressure continues to decline with age. PSMI may occur in any breed of dog or in mixed breed dogs but some breeds are overrepresented including the Doberman pinscher, Giant Schnauzer, Old English Sheepdog, Rottweiler, and Boxer. The German Shepherd and Dachshund are underrepresented in some reports of dogs with PSMI10. Labrador retrievers were underrepresented in another study11. PSMI is more common in large dogs (> 20 kg) in which the incidence of incontinence may be as high as 30%10. Bitches weighing more than 10 kg were nearly 4 times as likely to develop post-spay PSMI than those less than 10 kg 4. Urinary incontinence can occur before spaying in some breeds such as Greater Swiss Mountain dogs, Soft Coated Wheaten terriers, Dobermans and Giant Schnauzers. Urine leakage while the dog is sleeping or lying down is the most common historical finding in dogs with uncomplicated PSMI. Signs of lower urinary tract distress (e.g. increased frequency, straining, hematuria) typically are not present in dogs with PSMI unless complicated by UTI. UTI may develop in dogs with PSMI due to the wicking effect of a urine-soaked perineum and decreased host defenses against bacterial ascent associated with decreased urethral pressure. Physical examination findings usually are unremarkable in dogs with uncomplicated PSMI with the exception of urine scalding and urine soiling of the perineum. Routine laboratory tests such as urinalysis and urine culture are usually normal or negative. Phenylpropanolamine (PPA) is often prescribed as the initial treatment to restore urinary continence in dogs with PSMI by stimulating the alpha-adrenergic receptors along the urethra1. Incontinence is controlled in 75-90% of female dogs with PSMI treated with the α-adrenergic agonist PPA at a dosage of 1.0-1.5 mg/kg PO q12h or q8h (standard preparation). PPA is also available as a sustained release product (Cystolamine®; 75 mg capsule). More than half of the dogs that failed to respond with the standard formulation of PPA became continent when treated with a sustained release formulation of this drug12. Nearly all affected dogs have some improvement in continence after treatment with PPA. The largest dose should be given at night to control incontinence while the dog is sleeping. In dogs with incontinence only at night, dosing only at night can be effective. PPA may become less effective with prolonged use (socalled tachyphylaxis but decreased effectiveness over time could also be due to further decrement in MUCP). Potential adverse effects include restlessness, behavioral change, and hypertension. Relative contraindications include known underlying cardiac disease, chronic kidney disease, or systemic hypertension. We recommend systemic blood pressure be measured before beginning PPA treatment and periodically thereafter to identify the development of systemic hypertension. Pseudoephedrine was found to be an unsatisfactory alternative adrenergic treatment to PPA for PSMI in dogs13. Estrogens are an effective treatment for PSMI in many dogs and can be given much less frequently than PPA1. Incontinence is controlled in 60-80% of affected dogs treated with estrogens alone for PSMI3,14-19. Estrogen increases the sensitivity of urethral α-adrenergic receptors to catecholamines; they also may increase the number of receptors. The MUCP increased on the UPP after treatment with estrogens for a week in one study20, but has not been measured in nearly as many studies as with PPA treatment. Diethylstilbesterol (DES) is dosed at 0.1-1.0 mg (0.02 mg/kg) per dog PO for 3-5 days followed by 0.1-1.0 mg PO every 3 to 7 days. DES has become more difficult to obtain because it is no longer used in human patients but it is available from veterinary compounding pharmacies. Premarin® (conjugated estrogens - obtained from pregnant mare’s urine) is dosed at 20 μg/kg PO q3d or q4d. This drug contains sodium estrone sulfate (50-65%), and sodium equilin sulfate (20-35%); estrone is converted to estradiol. Although published information on the use of Premarin® in dogs with PSMI is lacking, we have had success with this product in our hospital. Oestriol (Incurin®; a naturally-occurring, short-acting estrogen; licensed for use in incontinent neutered female dogs in the USA by the FDA as of July 2011 and in Europe since 2000) is dosed at 2 mg per dog per day for 1 week followed by reduction to minimally effective daily dose (0.25 to 2.0 mg per dog per day) and finally alternate day dosing (dose not related to body weight). In one study, 61% of dogs achieved continence and 22% improved for an overall response rate of 83% with oestriol treatment; no hematologic abnormalities were identified17. Similar beneficial outcomes were shown in the as of yet unpublished series of dogs used to gain FDA approval in the USA for estriol treatment of PSMI to control estrogen-responsive urinary incontinence in ovariohysterectomized female dogs(Freedom of Information Summary Original New Drug Application; NADA 141-435 Incurin (Estriol) Tablets Dogs Approved July 25, 2011). Potential complications of treatment with estrogens include induction of the clinical signs of estrus, perineal alopecia, and bone marrow suppression. We have not encountered bone marrow suppression in dogs receiving low dose intermittent estrogens; this is most often seen after use of long-acting injectable estrogens such as estradiol cypionate or with overdose. Urethral bulking agents delivered through a cystoscope can be effective in the treatment of PSMI in dogs. Successful implantation of urethral bulking agents avoids the need for daily medication. The bulking agent and implantation process are expensive, requires general anesthesia, and may not have long duration of effect in some dogs. Successful implantation requires special equipment and technical expertise. Submucosal urethral collagen injections improve continence in most dogs that have failed PPA treatment for PSMI. A 50-80% response rate with collagen alone as treatment is reported21,22. Collagen injections often render PPA more effective than prior to collagen injections in dogs not completely continent after collagen injections. The use of a urethral hydraulic occluder as an artificial urethral sphincter (AUS) has recently been developed for clinical use in dogs. This minimally invasive surgical technique is currently offered in our practice as the first option for most dogs with PSMI that have failed medical treatment or other surgery.23,24. Data from 18 female dogs with PSMI and 3 female dogs with PSMI and pelvic bladder were reported to obtain about a 90% success rate for major improvement in urinary continence scores lasting long time periods following placement of the AUS25. It appears that the use of permanent implants results in a more durable and consistent urethral compression than that achieved with other treatment modalities. Owners should be warned that partial urethral obstruction could occur in some dogs over time that will require removal of the AUS. Ectopic Ureter(s) Ectopic ureter is the most common anatomic abnormality causing urinary incontinence in female dogs. Ectopic ureter is diagnosed when ureteral openings terminate anywhere else than in their normal location in the trigone. Though ectopic ureter is often viewed as a simple plumbing bypass problem, it is at times more complex in that it can be associated with a short urethra, low urethral closure pressure (PSMI), and poorly described abnormalities in the formation of the urethra-vesicular junction. Abnormalities in the development of the kidney (single agenesis, renal hypoplasia) are encountered in some dogs as well as the finding of hydronephrosis and hydroureter. Urinary tract infection can occur in the lower urinary tract and also in the kidneys (pyelonephritis) due to the predisposing anatomical abnormality and effects of obstruction. So it is important to evaluate the entire urinary tract in those with suspected ectopic ureter(s). Patients are usually young at presentation (< 1 year of age; females tend to be presented at a younger age than males). Females are diagnosed more often than males. Urinary incontinence is the most common clinical sign in both female and male dogs with EU, but some are diagnosed as an incidental finding in those without incontinence (usually EU termination points that are in an abnormal position in the bladder or in the proximal urethra). The degree of urinary incontinence is variable ranging from mild and intermittent to continuous and severe. Incontinence may worsen in recumbent positions, with increased activity, and with increased water consumption (swimming, eating snow, drug therapy i.e. steroid administration). The severity of urinary incontinence does not indicate whether the ectopia is unilateral or bilateral, where the ectopic ureteral orifice(s) terminate, or treatment outcomes. Bilateral displacement of the ureteral orifices is detected more often than unilateral; early reports of primarily unilateral involvement likely were affected by limitations of imaging (i.e. lack of urethrocystoscopy). Termination points in those with bilateral EU may not be located at the same site (e.g. proximal and mid urethral; proximal and distal urethral). A diagnosis of ectopic ureter should be made if the ureteral orifice is displaced even minimally from its normal position in the trigone. Most ectopic ureters in female dogs terminate in the urethra after tunneling from more proximal locations 28. Ectopic ureters may have their terminal opening still within the bladder, at the vesico-urethral junction, proximal to distal urethra, and the vestibule. Extramural ectopic ureters have been reported rarely until recently27. Ectopic ureters are more common in certain breeds including Siberian huskies, Labrador retrievers, Golden retrievers, Soft-Coated Wheaten terriers, Newfoundlands, Welsh Corgi, and Poodles of any size. Related Entlebucher Mountain Dogs affected with ectopic ureter(s) have recently described both with and without urinary incontinence 26. Multiple reports document the diagnosis of EU in littermates, half siblings and other related family members. As a note of clinical interest, the Doberman pinscher, another breed over represented with juvenile urinary incontinence is not affected by EU but instead by familial PSMI. It has been reported that a specific breed diagnosed with EU can affected the prognosis and outcome of surgical treatment. All 16 Labrador retrievers diagnosed with EU in recent study regained continence after surgical repair27. Excretory urography has long been considered the best method of diagnosis for EU in primary care practice. Excretory urography can establish a diagnosis of ectopic ureter but failure to identify an ectopic ureter on excretory urography does not eliminate the possibility of one being present. Both false positive and false negative results may occur especially if performed without fluoroscopy at the same time. Oblique positioning of the patient, concurrent negative contrast cystography, and fluoroscopy all can aid in identification of an ectopic ureter. However, the definitive diagnosis of ureteral ectopia often remains elusive following appropriate radiographic evaluation. Fluoroscopy and retrograde vaginourethrography may provide additional information regarding structure of the urethra, distal ureteral morphology and confirmation of pelvic bladder syndrome. Observing the typical “J” configuration of the ureter as it dorsally enters the trigone does not guarantee that the ureter opens into the bladder at the normal location at the trigone. Contrast enhanced CT is considered to be the standard for diagnosis of EU in male dogs and equal to that of uroendoscopy in female dogs30. Transurethral cystoscopy is the gold standard for the diagnosis of ectopic ureters in female dogs 28. A definitive diagnosis of ectopic ureter is made during urethrocystoscopy by visualization of additional openings in the urethra or vestibule. The ectopic ureter termination point is classified as at the vesicourethral junction, proximal urethra, mid-urethra, distal urethra, in the vestibule, or still within the bladder but not in the usual trigone area. The ectopic ureteral openings in the urethra are always located dorsally or dorsolaterally as a consequence of the abnormal embryologic migration pattern. Treatment of Ectopic Ureter(s) Numerous surgical procedures have been published in the veterinary literature focusing on reestablishment of ureteral anatomy within the bladder lumen (ureteral transposition, neoureterostomy and laser ablation of intramural ureters), rerouting urine flow proximal to the urethral sphincter mechanism. Improved continence (as high as 100%) has been demonstrated in several studies involving surgical and minimally invasive treatment of EU in male dogs. Failure to adequately control urinary continence has plagued the success of all published procedures to correct EU in female dogs. Surgical transposition of the ureter is helpful in controlling incontinence but post surgical incontinence occurs in at least 50% of affected female dogs35,36. Urethral bulking agents and AUS both help to control urine leakage by increasing the basal pressure of the urethra. Submucosal urethral collagen injections can be used with success in some dogs with ectopic ureters that continue to have urinary incontinence after conventional surgery. The use of urethral bulking treatment with collagen was reported in 5 female dogs following unsuccessful ectopic ureteral surgery; it was also used in 5 female dogs instead of surgery for dogs with proximally located ectopic ureters. The degree of urethral coaptation following collagen implantation was less complete in dogs with previous ectopic ureter surgery likely due to the effects of previous surgery and scarring making the submucosal injections more difficult 22. Endoscopic laser ablation of ectopic ureters has recently been reported as a minimally invasive procedure to reestablish the ureteral orifice(s) within the bladder at the trigone. The laser is used to ablate the intraluminal portion of the submucosal ureter creating a neoureterostomy in a more normal trigonal position. Continence was reported for a median of 18 months in 4 of 4 male dogs following laser ablation of ectopic ureter37. In 13 female dogs that were able to be evaluated following laser ablation for ectopic ureter, 4 were completely continent without drugs, 5 were completely continent with drugs, and 4 improved on PPA but were still incontinent38. Laser ablation is not expected to result in complete remission of incontinence in some dogs with ectopic ureters that have an associated PSMI. For those with persisting incontinence following laser ablation or other surgical procedures, urethral bulking agents 22 and placement of an AUS39 remain options for further treatment. In 8 female dogs with ectopic ureter that had persisting urinary incontinence following ectopic ureter surgery or urethral collagen implantation, the degree of urinary incontinence improved following placement of an AUS39. In 6 female dogs of another study that failed to gain continence following surgical repair (4 following neoureterocystostomy and 2 after laser ablation of intramural EU), placement of an AUS resulted in markedly improved continence in 5 of the 6 dogs25. REFERENCES 1. Arnold S, et. al. Reproduction in domestic animals 2009;44 Suppl 2:190-2. Stocklin-Gautschi NM, et. al. Journal of reproduction and fertility 2001;57:233-6. 3. Veronesi MC, et. al. 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